the use of botox injection in the treatment of the ( 50 ... · 1 the use of botox injection in the...

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The Use of Botox Injection in the Treatment of the

Neurogenic Bladder

• Dr C K Chan• Division of Urology

• Department of Surgery• Prince of Wales Hospital

Neurologic diseaseDementia ( 30- 100% )Parkinson’s disease ( 38 – 70% )Stroke ( 20 – 50% )Cerebral tumour ( 24 % )Cerebral palsy ( 36% )Shy-Drager syndrome ( 100% )

Multiple sclerosis ( 50 – 90% )Traumatic injury ( majority )HaematomasyringomyeliaCompression (e.g. tumour, Cervical spondylosis) ( 28 – 87% )EAU guidelines

2003 / 2006Disc prolapse ( 6 – 18% ) ( 28 – 87% )MyelitisSpina bifida ( 90 – 97 % )

Sacral agenesisCauda equina diseasePelvic diseasePelvic surgery ( 10 – 60% )Childbirth injuryDiabetes mellitus ( 35 – 50% , type 2 : 87% ) Alcohol Abuse ( 5 – 60% )

2003 / 2006

2000 – 1000 B.C.

‘….one having a dislocation in a vertebra of his neck, while he is unconscious of his two legs and two arms and his urine dribbles. An ailment not to be treated.’

Mortality of spinal cord injury due to renal problems in the past 90 years ( Donnelly J et al 1972; Borges PM et al 1982)Balkan War

(1912 – 1913)

95%World War I ( 1914 –1918 )80%

World War II (1939-1945 )40%

Korean War

Foley, June 1935

( 1950 – 1953 ) 25%

Vietnam War (1964-1975)

5-10%

Life expectancy for persons who survive theLife expectancy for persons who survive the11stst year post spinal cord injury ( years)year post spinal cord injury ( years)( National spinal cord injury database USA)

Age at injury NO i l

Functional at l l

Paraplegia Tetraplegia Tetraplegia Ventilator

1995

spinal cord injury

any level ( C 5-8 ) ( C 1-4 ) Dependent at any level

20 57.2 52.5 46.2 41.2 37.1 26.8

40 38.4 34.3 28.7 24.5 21.2 13.7

60 21.2 18.1 13.7 10.6 8.4 4.0

Bladder ( Sphincter ) Dysfunction

ƒ( t , l , c )

t = time from diease / injury,l = level of disease / injury, c = completeness of disease / injury

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Neurologic disease Bladder dysfunctionDementia Inappropriate toilet behaviourParkinson’s disease Detrusor hyper-reflexia + co-ordinatedStroke external urethral sphincter andCerebral tumour bladder neck activity

Cerebral palsy IncontinenceShy-Drager syndrome( Multiple System Atrophy )

Multiple sclerosis Hyper-reflexic with UNcoordinatedTraumatic injury external urethral sphincter andCompression Uncoordinated bladder neck(e.g. tumour, ( Autonomic dys-reflexia if lesion ( g , ( y fCervical spondylosis) above T6 )Myelitis Sensory impairmentSpina bifida Incontinence / incomplete

bladder emptying

Sacral agenesis Areflexic / underactive bladder withCauda equina disease denervated / underactive sphincterPelvic disease BUT coordinated bladder neckChildbirth injury Sensory impairmentDiabetes mellitus Incontinence / incomplete

bladder emptying

Level of Spinal Cord Dysfunction in Relation to Vesico-Urethral D sf nctionDysfunction

Spinal Cord InjurySpinal Cord InjuryIncidence of spine injury by highest level( Northwestern University Acute Spine Injury Centre 1972-1990) Meyer 1994

Completetetraplegia 25%

Incompletetetraplegia 25%

Completeparaplegia 25%

Incompleteparaplegia 25%

Urinary problem in spinal cord dysfunctionUrinary problem in spinal cord dysfunctionUrodynamic findings by level(s) of spinal cord injury.

Spinal level No. of pts D H +DESD +

D H +DESD -

D A Normal

cervical N=104Blavivas 1996 55% 30% 15% 0%N=114Weld 2000 68% 42% 0% 0%

Thoracic N=87Blavivas 1996 90% 10% 0% 0%N=54Weld 2000 50% 50% 0% 0%

Lumbar N=61Blavivas 1996 30% 30% 40% 0%N=28Weld 2000 39% 32% 21% 4%

sacral N=32Blavivas 1996 12% 12% 64% 12%N=14Weld 2000 14% 14% 86% 0%

mixed N=33Weld 2000 45% 33% 27% 3%

DH= detrusor hyper-reflexia ; DESD=detrusor external sphincter dys-synergiaDA=detrusor areflexia

Neurogenic Detrusor OveractivityDetrusor external sphincter dys-synergia

Normal VoidingInitial Management of Neuropathic Bladder

Level of lesionPeripheral n lesionPelvic operationLumbar disc prolapse

Suprasacral infrapontine LesionTrauma / multiple sclerosis

SuprapontineLesionParkinson’s diseaseCVA

ClinicalAssessment

General AssessmentVoiding diary / questionnaire ; QoL ; Physical ExamiationUrinalysis / urine culture -> treat UTI if presentUrinary tract imaging, renal functionPVR by u/s

Presumed diagnosis

Sphincter deficiency

Poor voiding

Neurogenic detrusor overactivity

Intermittentcatheterization

BehaviouralModificationAnti-muscarinics

External applianceIndwelling catheterSP catheter

Treatment

Cooperative ptMobile pt

Uncooperative ptImmobile pt

Specialized Management

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Specialized Management of Neuropathic Bladder

Level of lesionPeripheral n lesionPelvic operationLumbar disc prolapse

Suprasacral infrapontine LesionTrauma / multiple sclerosis

SuprapontineLesionParkinson’s diseaseCVA

ClinicalAssessment

Urodynamics ( VCMG / EMG )Urinary tract imaging

DiagnosisSphincter deficiency

Poor voiding

Neurogenic detrusor overactivity

ICAlpha blockerIntravesical electrostimulation

Triggered voidingAnti-muscarinicsICNeurostimulation

Anti-muscarinics ICSDAF + ICSDAF + SARSSphincterotomyBladder Augmentation + ICUrinary diversion

Treatment

No DESD DESD +

Timed voidingExt. applianceBulking agentsAUSSling

SuprapontineNDO

BehaviouralModificationAnti-muscarinicsNeurostimulationBladder augmentationExt appliancesICAnti-muscarincs

SDAF : sacral deafferenationSARS : sacral anterior root stimulationIC : intermittent catheterizationDESD : detrusor external sphincter dys-synergia

Adverse Effects of Oral Anti-muscarinics

• dry mouth,• tachycardia,

• blurred vision, • gastrointestinal effects

• (narrow angled ) glaucoma +( g ) g• CNS effect e.g. poor concentration, confusion

The most common adverse effect is dry mouth

But blurred vision and CNS effects will render patients to discontinue medication

Intravesical Therapiesfor Neuropathic Bladder

Apart From Oral pPharmacotherapay

Intravesical Oxybutynin

Buyse et al 1985Brendler et al 1989Greenfield et al 1991Madersbacher et al 1995Haferkamp et al 2000

Buyse et al Eur J Ped Surg 1985 ; 5 ( Suppl. 1 ) 31 - 34Brendler et al J Urol; 141: 1350 – 1351Greenfield et al J Urol 1991 ; 146 : 532 - 534Madersbacher et al Eur Urol 1995 ; 28 : 340 – 344Kaplinsky et al J Urol 1996 ; 156 : 753 – 756Haferkamp et al Spinal Cord ( 2000 ) 38, 250 - 254

0.2 – 0.4 mg / kg per day5 mg oxybutynin / 15 ml Normal SalineKeep in bladder till next catheterization61 - 87% continence rate


Haferkamp et al Spinal Cord ( 2000 ) 38, 250 - 254


Guerra: J. urol., Volume 180(3).September 2008.1091–1097

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Capsaicin ( 1989 ) /

16 x 106 UnitsScoville Heat Scale

Micturition reflex in neurologic disease:

Predominant afferent input from bladder is through C-fibre

Vanilloid receptor 1Non-selective ion channelIntravesical instillationInitial stimulation-> pain +++then desensitizes C-fibreLong-lasting suppression

30000-50000U

Capsaicin 1mM; 100ml ; 30min; LA / GA

( ICS committee 2002 )

Pretreatment Post-treatmentcapacity capacity144ml 267ml(72-195) (185-321)

Subjective clinical improvement72% ( 40 – 100%)

Capsaicin Petersen et al : NO benefit

Lazzeri et al:NO benefitAutonomic dys-reflexia 12.96%Urgency incontinence 35.18%Pain 96%

de Seze et al:When diluted in glucidic acid, few adverse events

Petersen et al Scand J Urol Nephrol. 1999; 33: 104 – 10Lazzeri M et al Spinal Cord 1999; 37 : 440 – 3Lazzeri M et al Urol Int 2004; 72: 145 – 9de Seze et al J Urol 2004 ; 171 : 251 - 5

Capsaicin / Resiniferatoxin1mM; 100ml ; 30min; LA / GA 1000x more potent sensory antagonist

VR-1

NO prior excitatory effect-> “NO PAIN”

Direct desensitizationDirect desensitization

100ml 50-100nM in 10% alcohol solutionInstillation for 30 min

Pretreatment post-treatmentcapacity capacity175(±36) ml 281(±93) ml (Lazzeri et al 1998)

Incontinence decreased by 1 – 2 episodes (Rivas et al 1999)

Capsaicin / Resiniferatoxin

-Reduction of nerve density of suburothelial innervations-Reduction in the expression of TRPV1 and P2X receptors

Brady C.M. et al Eur Urol 2004 ; 46 : 247 – 53Brady C.M. et al BJU Int 2004; 93 : 770 - 6

efficacy of improvement 92%

Silva et al 2000 Eur Urol 38: 444 - 52

Degree of neurological deficit

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Time line of the discovery of Clostridium Botulinum toxin and its medicinal use

1817: German physician and poet Justinus Kerner described botulinium toxin, using the terms "sausage poison" and "fatty poison", as this bacterium often causes poisoning by growing in badly handled or prepared meat products.

1870: Müller (another German physician) coined the name botulism from Latin botulus = "sausage".

1895: Prof. Pierre Emile van Ermengem of Ellezelles first isolated the bacterium Clostridium botulinum.

( Gram +ve , rod-shaped anaerobic Clostridium botulinum )

1923 Dickson et al ; Effect of botulinum toxin upon the autonomic nervous system

1944: cultured Clostridium botulinum and isolated the toxin

1949: Burgen's group discovered that botulinum toxin blocks neuromuscular transmission

1973: Alan B Scott used botulinium toxin type A (BTX-A) in monkey experiment

1980: Alan B Scott used BTX-A for the first time in humans to treat strabismus

1989: BTX-A (BOTOX) was approved by the US FDA for the treatment of strabismus, blepharospasm, and hemifacial spasm in patients over 12 years old

2002: FDA announced the approval of botulinum toxin type A (BOTOX Cosmetic) to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines).

Time line of the discovery of Clostridium Botulinum toxin and its medicinal use in Urology

1967 Carpenter ; motor responses of bladder following botulinum toxin intoxication in cats

1999: Stohrer et al ; detrusor hyper-reflexia

2000: Schurch et al ; detrusor hyper-reflexia in spinal cord injured patients

2002: Reitz et al ; 184 patients with detrusor hyper-reflexia treated with botulinum toxin injection

Immunological subtypes of Botulinum ToxinInternational Standards for Clostridium botulinum AntitoxinA Clostridium botulinumB Clostridium botulinumC1 Clostridium botulinumD Clostridium botulinumE Clostridium butyricumF Cl t idi b tiiF Clostridium baratiiG Clostridium argentinense

1 gm aerosolized botulinum toxin can kill 1.5 million population1 ng = 20 units1 unit = 0.05 ngLethal dose for 70 kg human : 0.09 – 0.15 ug ( IV / IM )

0.70 – 0.90 ug ( inhalation )70 ug ( po )

Immunological subtypes of Botulinum ToxinA, B, C1, D, E, F, and G

Botulinum type A toxin ( BTX-A):Botox® USADysport® United Kingdom

Botulinum type B toxin ( BTX-B):Myobloc® USAyNeuroBloc® Europe

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Blockade of the motor and autonomic cholinergic junctions

Botulinum Toxin ( Botox ; Dysport; Myobloc )

BTX Protein Commercial Molecular Preparation FormulationSubtypes Target preparation Weight Units

(kDa)

BTX-A SNAP-25 BOTOX 900 100 Vacuum driedDysport 900 500 Lyophilized

BTX-B VAMP/ Myobloc 700 2500 SolutionSynaptobrevin 5000

10000

BTX-C Syntaxin N.A.BTX-D VAMP/ N.A.

Synaptobrevin Cellubrevin

BTX-E SNAP-25 N.A.BTX-F VAMP/ N.A.

SynaptobrevinCellubrevin

BTX-G VAMP N.A.

Inhibition of acetylcholine exocytosis by BTX-ASmith CP and Chancellor MB (2004) J Urol 171: 2128–2137.

Illustration depicting nerve pathways targeted by botulinum toxin to treat lower urinary tract dysfunction

The circle with shading represents the prostate gland and the rectangle with shading represents the external urethral sphincter. Positive (+) signs represent sites of nerve activity and the negative (-) sign with associated arrows depicts locations where botulinum toxin may have inhibitory effects. Botulinum toxin in urology: evaluation using an evidence-based medicine approach Christopher P Smith, George T Somogyi and Timothy B Boone Nature Clinical Practice Urology (2004) 1, 31-37

Afferent Denervation

A schematic diagram of ultrastructural components of the human bladder wallApostolidis A et al Eur Urol 2006 ; 49: 644-650

Afferent Denervation

BTX-A may inhibit neurotransmitter release and reduce sensory nerve excitability decrease urgency, frequency and pain

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Botulinum Toxin Detrusor Injection for Detrusor Hyperreflexia

Botulinum toxin ( Botox ; Dysport )

Intravesical injection forNeurogenic Detrusor Overactivity

flexible cystoscope superfine 27-gauge disposable needleBOTOX® (Allergan, Irvine, CA) Bladder wall, avoiding the trigone. 30 different injections, Each containing 10 units of BOTOX® (1 ml), equally spaced points 200 units vs 300 units



0.5 – 1.0 ml per injectionLarger dilution volume -> greater suburothelial diffusion-> BTX act on larger surface of detrusor

?? Extravasation ??

Avoid Trigone ?Avoid Dome ( intraperitoneal puncture -> bowel injury)

Outpatient vs Inpatient LA vs Anaesthesia

Continence rate according to the diluent volume



Cleveland Clinic Protocol ( Rackley et al 2005 )

Antibiotics100 ml 2% lignocaine -> bladder x 15 – 20 min10 units in 1 ml salineAvoid shaking ( to minimize disulphide bond disruption)Priming of needle sheath ( ~ 0.5 ml )Injection in even distributionSubmucosal injection vs direct detrusor injection



Schulte-Baukloh et al BJU Int 2005; 454



Schurch et al 2001

Max. bladder capacity296 -> 480 ml ( p<0.016)

Flexible injection needle ( 27G ) in use for giving intradetrusor botulinum toxin10 units / ml / site x 20 –30 sitessparing trigone

( p )

Max. detrusor voiding pressure65 -> 35 cmH2O ( p<0.016)

At 6 wks: 89.5% continentAt 36wks: 64.7% continent

? effect

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Before BTX-A Injection

After BTX-A Injection

Incontinence ( n ) 15 ( 100% ) 2 ( 13% )**

L k d l 700 ( 200 1800 ) 0 ( 0 250 )***

flexible cystoscope superfine 27-gauge disposable needleBOTOX® (Allergan, Irvine, CA) Bladder wall, avoiding the trigone. 30 different injections, Each containing 10 units of BOTOX® (1 ml), equally spaced points

Leaked volume ( ml/d )

700 ( 200 – 1800 ) 0 ( 0 – 250 )***

PdetMax ( cmH2O ) 86 ( 65 – 192 ) 35 ( 5 – 73 )***

Volume-Pdet < 40cmH2O ( ml )

185 ( 65 – 487 ) 434 ( 188 – 722 )

Max bladder capacity ( ml )

350 ( 79 – 719 ) 457 ( 345 – 722 )**

** p< 0.01, McNemar ; *** p< 0.005 , WilcoxonBagi et al 2004



Optimal dose ?Best method of injection ?Suburethral / intramural injection ?jDurability ?Outcome measure ?Cost – Benefit ?

?effect

Suburothelial injection100U 150U 200U

Difficult voiding ----- 50% 70%AROU ----- 10% 20%

Kuo et al AUA 2006 May 20-25 Abstract 347 ; Urology 2005 ; 66: 94 - 8

# T11; NDO ; incontinenceincontinence

3 months Post injection of Dysport to Detrusor

# T11

The Urodynamic Parameters at Baseline and after Botulinum Toxin Injection

Baseline Post-Botox Statistics*

Capacity (n=5) 331.4±148.8 333.2±155. 0.922

Qmax (n=5) 6.7± 6.7 9.4± 5.7 0.303

Voiding pressure (n=5) 62.0± 43.1 45.9±37.8 0.051

MUCP (n=5) 97.1±31.7 51.1±23.2 0.027

PVR (n=5) 225.4±174.4 110.1±137 0.07

MUCP=maximal urethral closure pressure, FPL=functional profile length,

PVR= postvoid residual volume

*Comparison between baseline and 4 weeks after treatment

Neurogenic Detrusor Overactivity

Schurch et al J Urol 2000; 164 ( 3Pt 1 ) : 692 - 7

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Neurogenic Detrusor Overactivity% patients who are completely continent following injection of BTX to bladder

50

60

70

80

nence

Tow et al Ann Acad Med Singapore 2007 ; 36; 11 - 7

0

10

20

30

40

50

pre-injection 6wk postBTX 26wk postBTX 39wk postBTX

%com

ple

te c

onti

Neurogenic Detrusor OveractivityUrodynamic changes following injection of BTX to bladder

400

500

600

n c

c


0

100

200

300

pre-inject ion 6wk postBTX 26wk postBTX

vo

lum

e in

mean reflex vo l .

mean cystometric capaci ty

Neurogenic Detrusor OveractivityUrodynamic changes following injection of BTX to bladder

40

50

60

70

essu

re c

mH

2O


0

10

20

30

40

pre-injection 6wk postBTX 26wk postBTX

max

imal

det

ruso

r pre

m ax pdet cmH2O

Neurogenic Detrusor OveractivityAuthors No. pts Dose ( U ) Outcome Duration ( months )

Bagi et al 2004 15 300 trigone sparing 87% dry; 13% minor leak; ↓pdetmax;

↑cystometric capacity

7 ( 4 – 12 )

Schurch et al 2000 21 2-300 trigone sparing 89% dry at 6 wk; ↑cystometric capacity;

↑mean reflex vol; ↓pdetQmax

9

Schurch et al 2005 59 2-300 trigone sparing Improved continence; ↑cystometric capacity;

↑mean reflex vol; ↓pdetmax

6

Reitz et al 2004 200 300 trigone sparing Improved continence; ↑cystometric capacity; ↑mean reflex vol. ;

↓pdetQmax

9

Schulte-Baukloh et al 2003

20 300 trigone sparing Improved continence; ↑cystometric capacity; ↑mean reflex volume;

↓pdetmax

6

Hajebrahimi et al 2005 10 3-400 trigone sparing Improved continence; ↑mean reflex volume; ↑cystometric capacity;

↓pdetmax

3+

Detrusor External Sphincter Dys-synergia

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BotoxDetrusor External Sphincter

Dys-synergia

First Report :First Report :Dysktra et al J Urol 1988 ; 139 : 919 – 22


Intravesical injection forDetrusor External Sphincter Dys-synergia

Antibiotics10 units in 1 ml salineAvoid shaking ( to minimize disulphide bond disruption)bond disruption)Standard cystoscope Collagen injection needlePriming of needle sheath ( ~ 0.5 ml )

Localization of external urethral sphincter : contraction of sphincter by patient / Valsalva manoeuvre 3, 6, 9, 12 o’clock vs 2, 10 o’clock

Injection of 3,6, 9, and 12 o’clock Position of Urethral Sphincter

NDO + DESD

NDO + DESD

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Pre-treatment

C5#, ASIA Class A, DH + DESDPoor bladder emptying, RU 426 ml

Reduced voiding pressure after botulinum A toxin injection

Reduced MUCP after Botulinum A toxin injection

Therapeutic Results after Botox Urethral Injection for Voiding

DysfunctionGoodGood ImprovedImproved FailedFailed

Detrusor underactivity (n=27)Detrusor underactivity (n=27) 13(48.2%)

8(29.6%)

6(22.2%)

DESD (n=18)DESD (n=18) 3(16.7%)

10(55.6%)

5(27.8%)(16.7%) (55.6%) (27.8%)

Dysfunctional voiding (n=18)Dysfunctional voiding (n=18) 6(33.3%)

10(55.6%)

2(11%)

Poor relaxation of urethral Poor relaxation of urethral sphincter (n=12)sphincter (n=12)

3(25%)

7(58.3%)

2(16.6%)

TOTAL (n=75)TOTAL (n=75) 25(33.3%)

35(43.7%)

15(20%)

DESD=Detrusor external sphincter dyssynergia Kuo et al 2002

9 months post-injection of Botox: resting UPP study

9 months post injection of Dysport to external urethral sphincter

CMG : 9 months post-injection of Botox/ Dysport( Dysport: 500 IU in 8 ml NS -> 62.5 ml in 1 ml NS ; 3ml injected )

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9 months following injection of Dysport to external urethral sphincter

CMG 2: 9 months post-injection of Dysport ( voiding phase )( Dysport: 500 IU in 8 ml NS -> 62.5 ml in 1 ml NS ; 3ml injected )

BotoxDetrusor External Sphincter Dys-synergia

Leippold et al Eur Urol 2003; 44: 165 - 174

Detrusor External Sphincter Dys-synergiaAuthors No. pts Dose ( U ) Outcome Duration ( months )

Dykstra et al 1988 11 20 – 240 ↓autonomic dysreflexia; ↓PVR; ↓UPP

2

Dykstra et al 1990 5 140 – 240 ↓autonomic dysreflexia; ↓PVR; ↓UPP

3

Schurch et al 1996 24 100 / 250 ↓UPP; NO ∆ autonomic dysreflexia

2-3 / 9-12

Gallien et al 1998 5 100 ↓autonomic dysreflexia; 40% able to do CISC

3 ( 3-5)

Rackley et al 2005 16 100 Improved UDI Score; improved bladder

perception scores; ↓PVR

3 – 6

S ith t l 2005 68 100 200 d t d CISC 6Smith et al 2005 68 100 – 200 ↓need to do CISC; ↓pdetmax; ↓PVR

6

Kuo et al 2003 20 50 ↓voiding pressure; ↓PVR; ↓UPP; improved QoL

3

Kuo et al 2003 103 50 – 100 87% discontinued CISC; ↓voiding pressure; ↓PVR;

↓UPP

4 ( 2 – 6 )

Phelan et al 2001 21 80 – 100 ↓PVR; ↓voiding pressure; 85% discontinued CISC

NA

Petit et al 1998 17 150 ↓CISC frequency; PVR unchanged; ↓voiding

pressure;

2 - 5

UDI : Urinary Distress Inventory

3 months following treatment ( injection to external urethral sphincter )

Pre-injection

CMG: 3 months post-injection of Dysport( Dysport: 500 IU in 8 ml NS -> 62.5 ml in 1 ml NS ; 3ml injected )

Botulinum toxin vs DESDBotulinum toxin vs DESD

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Botox Side Effects

Flu-like SymptomsUrinary Tract InfectionGeneralized Muscle Weakness ( 8 pts )

De Laet K et al Spinal Cord 43: 397 - 399

NeurostimulationBrindleySacral posterior root rhizotomy( sacral deafferentation )

Sacral anterior root stimulation( SARS )

intradurally

Supra-sacral lesion with intact efferent neurons and a bladder that is able to contract

Abolish reflex voiding

Extradurally

y

NeuromodulationBemelmans et al 1999‘… it is not really known how it works, however, there is strong evidence that neuromodulation works at a spinal and at a supraspinal level…’

Pain ?

Leakage due to detrusor hyperreflexia83% improved ( but still leakage ++ )

Voiding failure80% improved ( but still need intermittent catheterization)

£ ¥ € $

Urodynamics- Videourodynamics

CYK M/24 # T6, complete paraplegia, recurrent UTIincontinence

Team Work

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Thank You

the use of botox injection in the treatment of the ( 50 ... · 1 the use of botox injection in the...

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